Project Summary Respiratory Syncytial Virus (RSV) is the leading cause of viral death in infants and young children, and a major cause of respiratory illness in immune compromised adults and the elderly. Unfortunately, there is currently no vaccine or effective therapy available for RSV. Synagis, a monthly intramuscular injection of the monoclonal antibody (mAb) palivizumab, is the only FDA-approved intervention given to a very small subset of high-risk infants as immunoprophylaxis. However, it is not effective at treating RSV. Thus, for the tens of thousands of infants hospitalized for RSV, only supportive therapy is available, and morbidity and mortality are substantial. Interestingly, RSV spreads in the lung via shedding of virus exclusively into the airway; thus, RSV must traverse airway mucus (AM) before infecting neighboring cells, and RSV remains primarily restricted to the airways with little to no systemic viremia. We believe an RSV-specific, safe, effective and topically- delivered antiviral would provide a powerful option addressing the current gap in pharmacological interventions. Mucommune is developing RespiraClear to meet this goal, based on a proprietary ?muco- trapping? mAb technology platform with core claims allowed by the USPTO and exclusively licensed from UNC. RespiraClear is a topical mAb treatment based on (i) re-engineering RSV-binding mAb with elevated expression of a fully human Fc glycosylation that enhances its ability to trap RSV in AM and purges the virus from the airways via natural mucociliary clearance mechanisms, and (ii) stably delivering it to the lung airways using a vibrating mesh nebulizer. By concentrating an optimized mAb at the site of infection rather than delivering it systemically, we expect to enable efficacious and cost-effective treatment of RSV, with little risk of adverse side effects due to limited systemic adsorption from pulmonary delivery. Our pilot studies demonstrate that RespiraClear can potently trap RSV in human AM, facilitate rapid elimination of viral particles from the mouse lung airways, and remain stable when nebulized using a vibrating mesh nebulizer. Building off these promising results, we seek to verify in Phase I of this FastTrack proposal that RespiraClear is indeed superior to palivizumab injected intramuscularly in treating RSV infections in cotton rats, to date the most commonly used animal model for RSV infections. If successful, Phase II of the project will focus on accelerating the preclinical development of RespiraClear. This includes generating a stable CHO cell line for high yield production of RespiraClear (Aim 1), partnering with PARI (a leading nebulizer manufacturer) to develop a customized vibrating mesh nebulizer for RespiraClear (Aim 2A), validating its delivery performance in a pediatric lung model (Aim 2B), and finally, evaluating RespiraClear's efficacy in a neonatal lamb model (Aim 3). If successful, the proposed work will greatly accelerate the clinical evaluation of RespiraClear. The work will also help pave the way for improved, molecularly-targeted therapies against a broad spectrum of pathogens across all major mucosal surfaces.